Heart 96:1651-1655 doi:10.1136/hrt.2010.200121
  • Congenital heart disease

Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants

Open Access
  1. Judith A Goodship1
  1. 1Institute of Human Genetics, Newcastle University, Newcastle-upon-Tyne, UK
  2. 2Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  3. 3Bristol Children's Hospital, Bristol, UK
  4. 4Leeds General Infirmary, Leeds, UK
  5. 5Alder Hey Hospital, Liverpool, UK
  6. 6Great Ormond Street Hospital, London, UK
  7. 7Freeman Hospital, Newcastle-upon-Tyne, UK
  8. 8Institute of Medical Genetics, University of Zurich, Schwerzenbach-Zurich, Switzerland
  9. 9Institute of Child Health, London, UK
  1. Correspondence to Dr Judith Goodship, Institute of Human Genetics, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; j.a.goodship{at}
  • Accepted 30 June 2010


Background Tetralogy of Fallot (TOF) is common in individuals with hemizygous deletions of chromosome 22q11.2 that remove the cardiac transcription factor TBX1.

Objective To assess the contribution of common and rare TBX1 genetic variants to TOF.

Design Rare TBX1 variants were sought by resequencing coding exons and splice-site boundaries. Common TBX1 variants were investigated by genotyping 20 haplotype-tagging SNPs capturing all the common variations present at the locus. Association analysis was performed using the program UNPHASED.

Patients TBX1 exons were sequenced in 93 patients with non-syndromic TOF. Single nucleotide polymorphism analysis was performed in 356 patients with TOF, their parents and healthy controls.

Results Three novel variants not present in 1000 chromosomes from healthy ethnically matched controls were identified. One of these variants, an in-frame 57 base-pair deletion in the third exon which removed 19 evolutionarily conserved residues, decreased transcriptional activity by 40% in a dual luciferase assay (p=0.008). Protein expression studies demonstrated that this mutation affected TBX1 protein stability. After correction for multiple comparisons, no significant associations between common genetic variants and TOF susceptibility were found.

Conclusion This study demonstrates that rare TBX1 variants with functional consequences are present in a small proportion of non-syndromic TOF.


  • Funding This work was supported by the British Heart Foundation (RG/02/014); European Community's Sixth Framework Programme contract ('HeartRepair') (LSHM-CT-2005-018630); and the Federated Foundation; BK holds a British Heart Foundation Chair; HRG was supported by a Medical Research Council PhD studentship.

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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